AL amyloidosis is a bone marrow plasma cell dyscrasia, related to multiple myeloma and other monoclonal gammopathies, in which a mutant immunoglobulin light-chain is over-expressed and deposits in many organs. It is the most common form of systemic amyloidosis in the Unite States, estimated to occur in more than 5-12 persons/million/year. The Amyloid Research and Treatment Programs at Boston University has a strong record of research and is internationally as a referral center for patient treatment. We have pioneered aggressive treatment using intravenous melphalan and autologous stem cell rescue with promising results for AL amyloidosis, however less than half of the patients are eligible for such treatment. Without effective therapy, the median survival is poor, as amyloid deposition leads to progressive organ failure and death within a median of 110-18 months. The overall hypothesis of this Program Project Grant is that mutations in light chain genes give rise to protein modifications that interact with the host tissue environment that cause fibrillogenesis. The goals of this Program Project are to: identify the genetic and structural features of amyloidogenic light chains that lead to fibril formation; determine the responses of host tissues that promote amyloid deposition and organ failure; develop an animal model of AL amyloidosis; and exploit it for preclinical testing of immunotherapy. To reach these goals we will examine the expressed gene sequence and germline origin of amyloidogenic light chains found in our large referral population of patients with AL amyloidosis (Project 1). We will characterize the biophysical properties and structural conformation responsible for polymerization of the amyloid light chain protein (Project 2). We will analyze the amyloidogenic light chain protein themselves, their post- translational modifications, and their interacting molecules and tissue responses (Project 3). Using computer modeling we will predict fibrillogenic amino acids in models and test these in vitro and in an animal model (Projects 1-3). Novel approaches to treated based on immunotherapy will be developed and tested in the animal model (Projects 1 and 4). A sophisticated protein biochemistry and immunopathology core and a state-of-the-art mass spectrometry core provide essential support to the Program. These investigations will potentially benefit both our patients and those with other forms of amyloidosis including Alzheimer's disease.